Atherosclerosis, a chronic inflammatory disease, is still the number one cause of death in the United States. Numerous risk factors for the development of atherosclerosis have been identified, including obesity and hypertriglyceridemia. Superfund chemicals such as PHAs and PCBs also have been shown to increase the risk and incidence of cardiovascular diseases. Most of all, we have evidence that both selected PCBs and fatty acids can induce endothelial cell dysfunction and inflammation, critical events in the early pathology of atherosclerosis. Little is known about mechanisms and regulation of cellular uptake, trafficking and initiation of proinflammatory pathways by both PCBs and fatty acids. Membrane lipid rafts such as caveolae are particularly abundant in endothelial cells, where they are believed to play a major role in the regulation of endothelial vesicular trafficking. Thus, we hypothesize that caveolae are critical in the cellular uptake of fatty acids and lipophilic environmental contaminants such as PCBs. More recently, caveolae have also been implicated in the regulation of cell signal transductions. Thus, we hypothesize that PCBs and certain fatty acids interact with caveolae and trigger distinct proatherogenic signaling pathways, leading to endothelial cell dysfunction. We also hypothesize that these signaling pathways can be down-regulated by antioxidant nutrients and related bioactive compounds as well as by ligands of antiatherogenic nuclear receptors (PPARs). These hypotheses will be tested in vitro as well as in vivo by studying the interactions of PCBs with dietary compounds such as fatty acids and antioxidants. Importantly, we will use cell and mouse models lacking the caveolin gene to determine the involvement of caveolae in the PCB and fatty acid uptake and toxicity. We propose to explore mechanisms of nutrient-mediated modulation of PCB toxicity, and the outocome of our proposed study may lead to novel nutritional recommendations and therapeutic interventions in population exposed to Superfund chemicals.